Magnolol Enhances the Therapeutic Effects of TRAIL through DR5 Upregulation and Downregulation of c-FLIP and Mcl-1 Proteins in Cancer Cells

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 19; p. 4591
• Main Authors: Woo, Seon Min, Min, Kyoung-Jin, Kwon, Taeg Kyu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-10-2020; MDPI
• Subjects: A549 Cells; Antiangiogenics; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Bioactive compounds; Biological activity; Biphenyl Compounds - pharmacology; c-FLIP; c-FLIP protein; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Combined treatment; Down-Regulation - drug effects; Down-Regulation - genetics; DR5; FLICE-inhibitory protein; FLIP protein; HeLa Cells; Humans; Lignans - pharmacology; Liver cancer; Lung cancer; Lysosomes; magnolol; Mcl-1; Mcl-1 protein; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Neoplasms - drug therapy; Neoplasms - genetics; Poly(ADP-ribose) polymerase; Proteasome Endopeptidase Complex - genetics; Proteasomes; Protein expression; Proteins; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; siRNA; TNF-Related Apoptosis-Inducing Ligand - genetics; TRAIL; Transcription; Up-Regulation - drug effects; Up-Regulation - genetics; Mcl-1; TRAIL; magnolol; c-FLIP; DR5
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25194591

Magnolol is a biologically active compound, isolated from the Chinese herb
, that regulates antiproliferative, anticancer, antiangiogenic and antimetastatic activities. We found that magnolol sensitizes TRAIL-induced apoptotic cell death via upregulation of DR5 and downregulation of cellular FLICE-inhibitory protein (c-FLIP) and Mcl-1 in cancer cells, but not in normal cells. Mechanistically, magnolol increased ATF4-dependent DR5 expression at the transcription level, and knockdown of ATF4 markedly inhibited magnolol-induced DR5 upregulation. Silencing DR5 with siRNA prevented combined treatment with magnolol and TRAIL-induced apoptosis and PARP cleavage. Magnolol induced proteasome-mediated Mcl-1 downregulation, while magnolol-induced c-FLIP downregulation was regulated, at least in part, by lysosomal degradation. Our results revealed that magnolol enhanced TRAIL-induced apoptosis via ATF4-dependent DR5 upregulation and downregulation of c-FLIP and Mcl-1 proteins.